The mammalian immune system provides a means for the recognition and elimination of tumor cells, other pathogenic cells, and invading foreign pathogens. While the immune system normally provides a strong line of defense, there are many instances where cancer cells, other pathogenic cells, or infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity. Chemotherapeutic agents and radiation therapies have been developed to eliminate replicating neoplasms. However, most, if not all, of the currently available chemotherapeutic agents and radiation therapy regimens have adverse side effects because they work not only to destroy cancer cells, but they also affect normal host cells, such as cells of the hematopoietic system. The adverse side effects of the currently available anticancer drugs highlight the need for the development of new therapies specific for pathogenic cell populations and with reduced host toxicity.
Researchers have developed therapeutic protocols for destroying cancer cells by targeting cytotoxic compounds to such cells. Many of these protocols utilize toxins conjugated to antibodies that bind to antigens unique to or overexpressed by cancer cells in an attempt to minimize delivery of the toxin to normal cells. Using this approach certain immunotoxins have been developed consisting of antibodies directed to specific antigens on pathogenic cells, the antibodies being linked to toxins such as ricin, Pseudomonas exotoxin, Diptheria toxin, and tumor necrosis factor. These immunotoxins target tumor cells bearing the specific antigens recognized by the antibody (Olsnes, S., Immunol. Today, 10, pp. 291-295, 1989; Melby, E. L., Cancer Res., 53(8), pp. 1755-1760, 1993; Better, M. D., PCT Publication Number WO 91/07418, published May 30, 1991). Although the immunotoxins are directed to specific antigens on pathogenic cells, the toxin component of these compounds may exhibit toxicity to normal host cells. The use of vitamins to deliver chemotherapeutic agents to cells has also been described (see U.S. Pat. No. 5,416,016).
Another approach for targeting populations of cancer cells or foreign pathogens in a host is to enhance the host immune response against the pathogenic cells to avoid the need for administration of compounds that may also exhibit independent host toxicity. One reported strategy for immunotherapy is to bind antibodies, for example, genetically engineered multimeric antibodies, to the tumor cell surface to display the constant region of the antibodies on the cell surface and thereby induce tumor cell killing by various immune-system mediated processes (De Vita, V. T., Biologic Therapy of Cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, J. P., U.S. Pat. No. 5,672,486). However, these approaches have been complicated by the difficulties in defining tumor-specific antigens. Thus, there remains a significant need for effective therapies with minimized host toxicity directed to the treatment of disease states characterized by the existence of pathogenic cell populations in the affected host.
Mitomycins are natural products known to exhibit anti-tumor activity. Mitomycins can be produced by fermentation of Streptomyces caespitosus, and representive known mitomycins include mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin. The structures of these compounds are depicted by the following generic formula with substituents as shown in Table 1.

TABLE 1MitomycinXYZC-9AOCH3CH3HβBOCH3HCH3αCNH2CH3HβDNH2HCH3αENH2CH3CH3αFOCH3CH3CH3βJOCH3CH3CH3αPorfiromycinNH2CH3CH3β
Mitomycins are a class of cytotoxic drugs known as quinone-containing alkylating agents. Reduction of the quinone moiety results in the formation of bi-functional alkylating species that can form covalent bonds with a variety of cellular components including DNA. The interaction with DNA results in the formation of DNA crosslinks leading to the induction of apoptosis and cell death, and this interaction is thought to be the most important contributor to the anti-tumor activity of mitomycin compounds.